Altered function of the neurotransmitter, glutamate, has been implicated in many brain disorders, including ischemia (stroke), Alzheimer's disease and Huntington's disease. The cellular degeneration, caused by glutamate excitotoxicity, can be manifested as motor, sensory or learning disabilities. In this proposal, we will study the local and global effects of how neurons are affected by glutamate dysfunction using the spastic Han Wistar mutant which develops excitotoxicity in an age-dependent manner. This rat possesses a naturally occurring genetic mutation which shows an abnormal degeneration of neurons in two brain regions that are susceptible to glutamate toxicity: cerebellum and hippocampus. This proposal will address the various intracellular interactions that occur during excitotoxicity inherent produced in the sHW rat. Including: the potential role of intracellular calcium, the mode of cell death that is occurring in sHW cerebellum and hippocampus, mapping the glutamate receptor profile in the sHW CNS and examining the dimension of synaptic reorganization. In summary, we will experimentally follow the molecular and biochemical time course of neurological disorder, identifying how the central nervous system (CNS) reacts to the interactions of environment and the cells that are destined for degeneration. The potential benefit resulting from these experiments will be to ascertain the complex interactions of both the affected cell and those that may be affected by molecular and biochemical compensation. Ultimately, we believe that this research will lead to the establishment of new neuroprotective schemes for victims of glutamate excitotoxic disease.